The Role of Conventional Donor Lymphocyte Transfusions. Hans-Jochem Kolb 3rd Med. Dept. Klinikum re der Isar Technische Universitaet Muenchen Germany

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1 The Role of Conventional Donor Lymphocyte Transfusions Hans-Jochem Kolb 3rd Med. Dept. Klinikum re der Isar Technische Universitaet Muenchen Germany

2 Survival of Patients with Allogeneic SCT for AML CR1: N= 160 CR2: N= 47 >CR2/act dis.: N = 284 2

3 Relapse after Allogeneic Transplantation

4 Probability of Relapse of AML post Allogeneic SCT >CR2/rel.: N = 280 CR2: N = 47 CR1: N = 158 4

5 Adoptive Immunotherapy in Chimeras Allogeneic stem cell transplantation with T cell depletion Chimerism and tolerance Adoptive Immunotherapy with donor lymphocytes Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center for Environmental Health 5

6 Longterm Survival post Relapse of CML and Treatment with Donor Lymphocytes Hematological relapse N = 18 Cytogenetic/molecular relapse N = 32 Relapse in transformed phase: N = 25

7 Treatment of Relapse of AML after allogeneic SCT LD-AraC + PBSC + GM-CSF: N=36 DLT: N = 38 Chemo: N = 44 P<

8 Prophylactic DLT for high-risk AML - At least 30 days without immunosuppression - Free of GvHD and - No (severe) infections - Antibiotic, antiviral, antifungal prophylaxis? - Chimerism proven Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center 8

9 Preemptive DLI in AML Remission Patients > 180 days p trpl.

10 Preemptive DLI in AML Relapse Patients > 180 days p trpl.

11 Preemptive DLI in AML Relapse Patients Only patients without GVHD > 180 days p trpl., no GVHD

12 Differentiation of Leukemic Stem Cells PSC CFU-GEMM LSC? BFU-E CFU-GM CFU-MEG Pre-B Pre-T CFU-G Dendritic cells CFU-M PSC = pluripotent stem cell LSC = lymphoid stem cell 12

13 CART19 Cells in CLL Patients CD19 antibody variable CD3 ζ CD137 Produced by lentiviral transfection Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center for Environmental Health Porter et al NEJM

14 Use of Antibodies for Directing T Cells CD20 x CD3 rat-mouse monoclonal EpCAM x CD 3 rat-mouse monoclonal Blinatumomab (humanized) Single chain CD19 CD 3 Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center for Environmental Health 14

15 Bispecific Antibody (Bi20) IFN L CD20 CD3 T T Phagocytosis IFN TNFa Peptide presentation Macrophage/DC 15

16 % B cells Bi20 mediated B-CLL cell killing PBMC + CLL cells E:T 5:1 Patient 4, d3 of incubation, CD20-expression: MFI neg 0,5ng 5ng 50ng 250ng Bi20 TPBs01 Rituximab 16

17 % lysis T cell response against CLL cells T cell response against naive CLL cells CLL-HLAid CLL-HLAdif f K :1 40:1 E:T ratio 17

18 G/L Treatment of CLL relapse with Bi20 and DLT CLL cells in PB µg 10µg 20µg 40µg 80µg 160µg 320µg 600µg DLT Days 18

19 Treatment of Relapse with Bi20 and DLT in CLL and HG-NHL Nr Diagn Age/ Gender SCT DLI Stage Outcome 1 CLL 45 f Id sib 3 Refractory p53-deletion Transient disapp. P53-pos cells 2 HG-NHL 25 f Haplo-id - Refractory No progression for 4 mo no GVHD 3 HG-NHL 30 m Haplo-id - Refractory Refractory 4 HG-NHL 46 f Haplo-id. - refractory Refractory 5 CLL 57 m Id sib - 6 CLL 52 f Id sib - Refractory P53-deletion Refractory P53-deletion Transient response Transient response 19

20 B-CLL Patient 3-IG : Bioplex Bi20 Bi20 Bi DLI DLI DLI DLI Hu IL-2 Hu IL-4 Hu IL-8 Hu IL-10 Hu GM-CSF Hu IFN-g Hu TNF-a Hu IL-12 20

21 Role of Immunotherapy with DLI DLI are effective in myeloid leukemia with direct antigen presentation by dendritic cells of leukemia origin Effect may be improved by IFN-a and/or GM-CSF Low dose Ara-C / 5-Aza differentiation inducing chemotherapy Prevention of late relapses (> 180 days) in high risk AML, MRD-positivity Immune reconstitution after T cell depletion May be combined with (bispecific) antibodies in lymphatic malignancies Intensive chemotherapy prior to DLI and viral infections post DLI produce more severe GVHD DLI do require chimerism and no GVHD, they do not require gene transfer, they are easily available and not expensive

22 Problems with Preemptive DLI Too many patients on immunosuppression because of acute and chronic GVHD better T cell depletion and/or immunosuppression Early relapses in patients with FLT3-positive and MLLpositive leukemia better leukemia /myeloma control Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center for Environmental Health 22

23 Clinical Cooperative Group Hematopoietic Cell-Transplantation Dept. Med. III, Klinikum of the LM-University Helmholtz Center Munich - German Research Center for Environmental Health 3rd Dept of Medicine, Klinikum re der Isar, Techn. University Muenchen Clinical Unit G.Ledderose, J. Tischer, A. Rank, B. Heilmeier W. Hill, A. Hausmann M. Bergmann C. Schmid M. Schleuning E. Holler HCT - Laboratory R. Buhmann, H.Schmetzer, M. Freudenreich H. Adler, Y. Ting, D. Bund, A. Gallo, A. Arco-Zinneberg, M. Leeping, S. Sandner, A. Knauerhase, B. Maier Cooperation with: C. Falk, D. Schendel, I. Bigalke, E. Kremer A. Moosmann J. Adamski, A. Gallo F. Schuster, A. Borkhardt H. Lindhofer M. Stanglmaier, TRION M. Verbeek H. Menzel C. Mueller- Thomas Hematopoietic Cell Transplantation, Dept Medicine III, LM University of Munich, & Helmholtz Zentrum Muenchen - German Research Center 23

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